Benzofuran–isatin Hybrids: Design, Synthesis, and In Vitro Anti-cancer Activities

Article abstract of DOI:10.1002/jhet.3554

A series of novel benzofuran–isatin hybrids 6a–s tethered through propylene and butylene were designed, synthesized, and evaluated for their in vitro anti-cancer activities against HepG2 (liver carcinoma), Hela (cervical cancer), A549 (lung adenocarcinoma

Full text of DOI:10.1002/jhet.3554

Month 2019
Benzofuran–isatin Hybrids: Design, Synthesis, and
In Vitro Anti-cancer Activities
b
Quan-Ping Diao,a Hua Guo,a
and Gang-Qiang Wang
*
aSchool of Chemistry and Life Science, Anshan Normal University, Liaoning, Anshan, People’s Republic of China
bNon-power Nuclear Technology Collaborative Innovation Center, School of Nuclear Technology and Chemistry &
Biology, Hubei University of Science and Technology, Xianning, People’s Republic of China
*E-mail: wanggq@hbust.edu.cn
Received October 25, 2018
DOI 10.1002/jhet.3554
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel benzofuran–isatin hybrids 6a–s tethered through propylene and butylene were designed,
synthesized, and evaluated for their in vitro anti-cancer activities against HepG2 (liver carcinoma), Hela (cer-
vical cancer), A549 (lung adenocarcinoma), DU145 (prostatic cancer), SKOV3 (ovarian carcinoma), MCF-7
(breast cancer), and drug-resistant MCF-7/DOX (doxorubicin-resistant MCF-7) human cancer cell lines. The
majority of the synthesized hybrids displayed weak to moderate in vitro activities against the tested seven
cancer cell lines, but the enriched structure–activity relationship may pave the way for further optimization.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
[12] activities, which occupy an important position in the
development of new drugs. Benzofuran and isatin
derivatives also exhibit promising anti-cancer activities
[13–15], and some of them such as semaxanib (Fig. 1)
are under clinical trials or have already been used in
clinics for the treatment of various cancers [16,17].
Moreover, benzofuran and isatin derivatives also
demonstrate excellent physiochemical, toxicological, and
pharmacological properties in vivo, indicating its potential
for the treatment of cancers [7,18,19]. Therefore,
incorporation of benzofuran and isatin into one hybrid
may provide more effective anti-cancer candidates.
Cancer, a severe health problem that significantly
undermines life span and quality, has been threatened
form ancient time [1,2]. Cancer is the second leading
cause of death globally, and 9.6 million people worldwide
are estimated to die from cancer in 2018 [3]. The most
common types of cancer are lung, prostate, colorectal,
stomach, and liver cancer in men, while breast, colorectal,
lung, cervix, and thyroid cancer are the most common
among women [4]. Chemotherapy plays an important role
in the treatment of cancer, but the traditional cancer
chemotherapy develops resistance rapidly [5–7]. Thus, it
is imperative to develop new anti-cancer drugs.
Based on the aforementioned considerations and as a
continuous ongoing project,
a
series of novel
Benzofuran and isatin (indoline-2,3-dione) derivatives
possess a variety of biological properties such as anti-
bacterial [5,6], anti-tubercular [7–11], and anti-malarial
benzofuran–isatin hybrids tethered through propylene and
butylene were designed, synthesized, and evaluated for
their in vitro anti-cancer activities against HepG2
© 2019 Wiley Periodicals, Inc.

Q.-P. Diao, H. Guo, and G.-Q. Wang
Vol 000
(liver carcinoma), Hela (cervical cancer), A549 (lung
adenocarcinoma), DU145 (prostatic cancer), SKOV3
(ovarian carcinoma), MCF-7 (breast cancer), and drug-
resistant MCF-7/DOX (doxorubicin-resistant MCF-7)
human cancer cell lines. Preliminary studies on structure–
activity relationship study are also taken to facilitate the
further development of these hybrids.
RESULTS AND DISCUSSION
All of the desired benzofuran–isatin hybrids 6a–s can be
achieved by the synthetic route depicted in Scheme 1. 5-
Figure 1. Design strategy for benzofuran–isatin hybrids tethered via dif-
ferent linkers. [Color figure can be viewed at wileyonlinelibrary.com]
Scheme 1. Synthesis of benzofuran–isatin hybrids 6a-s.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Benzofuran–isatin Hybrids: Design, Synthesis, and In Vitro Anti-cancer Activities
Table 1
Structures and anti-cancer activities of benzofuran–isatin hybrids 6a–s.
IC50 (μM)
Compound
HepG2
Hela
A549
DU145
SKOV3
MCF-7
MCF-7/DOX
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
6.94
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
18.66
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
31.79
46.32
43.46
49.12
42.84
47.39
49.41
41.56
43.15
41.60
39.74
47.26
42.72
32.54
39.87
40.29
42.44
48.52
36.18
38.43
14.38
41.27
44.15
>50
48.63
43.86
>50
44.76
48.71
47.53
42.65
41.39
46.68
49.62
45.95
41.67
45.32
43.68
41.29
42.36
>50
6s
Etoposide
Methoxyisatin/5-fluoroisatin/isatin 1a–c were alkylated
with 1,3-dibromopropane and 1,4-dibromobutane in the
presence of potassium carbonate to give N-(3-
bromopropyl/4-bromobutyl)isatin derivatives 3a–e (yield:
63–87%) [19]. The benzofuran intermediates 5a–c were
obtained by cyclization of ethyl 3-(4-substituted phenyl)-
3-oxopropanoates 4a–c and benzoquinone with copper
(II) triflate (Cu (OTf)2) as catalyst [18]. Treatment of
isatin derivatives 3a–e and benzofuran intermediates 5a–c
with potassium carbonate as base generated the desired
benzofuran–isatin hybrids 6a–h (58–83%). Finally,
condensations of 6a–h with the corresponding amine
hydrochlorides in the presence of sodium bicarbonate
generated the rest benzofuran–isatin hybrids 6i–s
(18–73%).
The synthesized benzofuran–isatin hybrids 6a–s were
evaluated for their in vitro anti-cancer activities against
HepG2, Hela, A549, DU145, SKOV3, MCF-7, and drug-
resistant MCF-7/DOX by SRB assay [20]. IC50 values
were presented as the concentration of drug inhibition
50% cell growth and determined by at least three separate
tests and reported, and the results were presented in
Table 1.
the reference etoposide (IC50: 6.94–31.79 μM) against
HepG2, DU145, SKOV3, and MCF-7.
The structure–activity relationship results suggested that
substituents at R1 and R3 positions at isatin moiety and R2
position at benzofuran motif as well as the length of the
linker have great influence on the activity against breast
cancer cell lines MCF-7 and MCF-7/DOX: for R1
position, electron-withdrawing -F could improve the
activity, while electron-donating -OMe was detrimental to
the activity, and the relative contribution order was
-F > -H > -OMe; for R2 position, introduction of -F and
-OMe could increase the activity when compared with
the unsubstituted ones, and the relative contribution order
of the substituents was -F ≥ -OMe ≥ -H; for R3 position,
-NOMe > -O > -NOEt; for the linker, the longer
butylene linker was more favorable than the shorter
propylene linker.
Among the synthesized benzofuran–isatin hybrids,
hybrids 6m (IC50: 32.54 μM) and 6a (IC50: 41.27 μM)
were found to be the most active against MCF-7 and
drug-resistant MCF-7/DOX, respectively. It is worth to
notice that the resistance index values (IC50(MCF-7/DOX)
/
IC50(MCF-7) for the majority of the synthesized
)
It can be concluded from Table 1 that benzofuran–isatin
hybrids 6a–s only exhibited weak to moderate anti-cancer
activities against breast cancer cell lines MCF-7 and
drug-resistant MCF-7/DOX with IC50 ranging from 32.54
to >50 μM and were inactive against HepG2 (liver
carcinoma), Hela (cervical cancer), A549 (lung
adenocarcinoma), DU145 (prostatic cancer), and SKOV3
(ovarian carcinoma). All hybrids were less potent than
benzofuran–isatin hybrids 6a–s were around 1, indicating
that these hybrids may have novel action mechanism.
CONCLUSIONS
In conclusion, 19 novel benzofuran–isatin hybrids 6a–s
tethered via propylene and butylene were designed,
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Q.-P. Diao, H. Guo, and G.-Q. Wang
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1
synthesized, and evaluated for their in vitro anti-cancer
activities against a panel of human cancer cell lines. In
spite of all hybrids were inactive against HepG2, Hela,
A549, DU145, and SKOV3, some of them exhibited
moderate activities against breast cancer cell lines MCF-7
and drug-resistant MCF-7/DOX. The resistance index
values for the majority of benzofuran–isatin hybrids were
around 1, indicating that these hybrids may have novel
action mechanism.
yield: 77%. H NMR (400 MHz, DMSO-d6) δ 1.31 (3H,
t, J = 8.0 Hz, CO2CH2CH3), 2.12 (2H, t, J = 4.0 Hz,
─CH2─), 3.89 (2H, t, J = 4.0 Hz, ─CH2─), 4.12 (2H, t,
J = 4.0 Hz, ─CH2─), 4.32 (2H, q, J = 8.0 Hz,
CO2CH2CH3), 6.98 (1H, dd, J = 4.0, 8.0 Hz, Ar─H),
7.24–7.28 (1H, m, Ar─H), 7.36–7.41 (2H, m, Ar─H),
7.44–7.42 (2H, m, Ar─H), 7.60 (1H, d, J = 12.0 Hz,
Ar─H), 8.01–8.04 (2H, m, Ar─H). ESI–MS m/z: 528
[M + Na]+. Elemental Anal. Calcd (%) for C28H21F2NO6:
C, 66.53; H, 4.19; N, 2.77. Found: C, 66.31; H, 4.05; N,
2.53.
Ethyl
5-(3-(5-methoxy-2,3-dioxoindolin-1-yl)propoxy)-2-
EXPERIMENTAL
phenylbenzofuran-3-carboxylate (6c). Yellow solid, yield:
59%. 1H NMR (400 MHz, DMSO-d6) δ 1.42 (3H, t,
J = 8.0 Hz, CO2CH2CH3), 2.24–2.27 (2H, m, ─CH2─),
3.85 (3H, s, OCH3), 4.00 (2H, t, J = 8.0 Hz, ─CH2─),
4.13 (2H, t, J = 8.0 Hz, ─CH2─), 4.42 (2H, q,
J = 8.0 Hz, CO2CH2CH3), 6.90 (1H, dd, J = 4.0, 8.0 Hz,
Ar─H), 6.99–7.02 (3H, m, Ar─H), 7.07–7.11 (1H, m,
Ar─H), 7.38 (1H, d, J = 12.0 Hz, Ar─H), 7.50–7.55
(2H, m, Ar─H), 7.59–7.61 (1H, m, Ar─H), 8.00–8.02
(2H, m, Ar─H). ESI–MS m/z: 522 [M + Na]+. Elemental
Anal. Calcd (%) for C29H25NO7: C, 69.73; H, 5.04; N,
Synthesis.
N-(3-bromopropyl/4-bromobutyl)isatin
derivatives 3a–e (yield: 63–87%) [21] and ethyl 2-(4-
substituted phenyl)-5-(prop-2-yn-1-yloxy)benzofuran-3-
carboxylate 5a–c were prepared via literature methods
[18,19].
A mixture of N-(3-bromopropyl/4-bromobutyl)isatin
derivatives 3a–e (1.0 mmol), ethyl 2-(4-substituted
phenyl)-5-(prop-2-yn-1-yloxy)benzofuran-3-carboxylate
5a–c (1.0 mmol), and K2CO3 (3.0 mmol) in DMF (50 mL)
was stirred at room temperature for 48 h. After filtration,
the filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
with PE:EA = 1:1 to give the desired benzofuran–isatin
hybrids 6a–h.
2.80. Found: C, 69.71; H, 4.87; N, 2.65.
Ethyl 2-(4-fluorophenyl)-5-(3-(5-methoxy-2,3-dioxoindolin-
1-yl)propoxy)benzofuran-3-carboxylate (6d). Yellow solid,
1
yield: 76%. H NMR (400 MHz, DMSO-d6) δ 1.31 (3H,
t, J = 8.0 Hz, CO2CH2CH3), 2.12 (2H, t, J = 4.0 Hz,
─CH2─), 3.76 (3H, s, OCH3), 3.87 (2H, t, J = 4.0 Hz,
─CH2─), 4.12 (2H, t, J = 2.0 Hz, ─CH2─), 4.32 (2H, q,
J = 8.0 Hz, CO2CH2CH3), 6.98 (1H, dd, J = 4.0, 8.0 Hz,
Ar─H), 7.14–7.20 (3H, m, Ar─H), 7.37–7.42 (3H, m,
Ar─H), 7.60 (1H, d, J = 12.0 Hz, Ar─H), 8.01–8.05
(2H, m, Ar─H). ESI–MS m/z: 540 [M + Na]+. Elemental
Anal. Calcd (%) for C29H24FNO7: C, 67.31; H, 4.67; N,
2.71. Found: C, 67.09; H, 4.51; N, 2.62.
The mixture of hybrids 6a–h (1 mmol), sodium
bicarbonate (2 mmol), and the corresponding amine
hydrochlorides (1.5 mmol) dissolving in water (10 mL)
and tetrahydrofuran (30 mL) was stirred at 60°C for 12 h.
After cooling to room temperature, the mixture was
extracted with EA (20 mL × 3). The combined organic
layers were washed with water (50 mL × 2) and brine
(50 mL) and then dried over Na2SO4. After filtration, the
filtrate was concentrated under reduced pressure to give a
residue, which was further purified by silica gel
chromatography eluted with PE: EA = 1:8 to give the rest
desired benzofuran–isatin hybrids 6i–s (18–73%).
Ethyl
5-(3-(2,3-dioxoindolin-1-yl)propoxy)-2-(4-fluoro-
phenyl)benzofuran-3-carboxylate (6e).
Yellow solid,
1
yield: 83%. H NMR (400 MHz, DMSO-d6) δ 1.31 (3H,
t, J = 8.0 Hz, CO2CH2CH3), 2.13 (2H, t, J = 8.0 Hz,
─CH2─), 3.89 (2H, t, J = 4.0 Hz, ─CH2─), 4.12 (2H, t,
J = 4.0 Hz, ─CH2─), 4.33 (2H, q, J = 8.0 Hz,
CO2CH2CH3), 6.98 (1H, dd, J = 4.0, 8.0 Hz, Ar─H),
7.11 (1H, t, J = 4.0 Hz, Ar─H), 7.24 (1H, d, J = 8.0 Hz,
Ar─H), 7.37–7.42 (3H, m, Ar─H), 7.54–7.64 (3H, m,
Ar─H), 8.01–8.05 (2H, d, J = 8.0 Hz, Ar─H). ESI–MS
m/z: 510 [M + Na]+. Elemental Anal. Calcd (%) for
C28H22FNO6: C, 68.99; H, 4.55; N, 2.87. Found: C,
68.76; H, 4.39; N, 2.69.
Ethyl
5-(3-(5-fluoro-2,3-dioxoindolin-1-yl)propoxy)-2-(4-
methoxyphenyl)benzofuran-3-carboxylate (6a).
Yellow
1
solid, yield: 69%. H NMR (400 MHz, DMSO-d6) δ 1.33
(3H, t, J = 4.0 Hz, CO2CH2CH3), 2.11 (2H, t, J = 4.0 Hz,
─CH2─), 3.85 (3H, s, OCH3), 3.89 (2H, t, J = 4.0 Hz,
─CH2─), 4.12 (2H, t, J = 4.0 Hz, ─CH2─), 4.33 (2H, q,
J = 4.0 Hz, CO2CH2CH3), 6.94 (1H, dd, J = 4.0, 8.0 Hz,
Ar─H), 7.09 (2H, d, J = 4.0 Hz, Ar─H), 7.25–7.28 (1H,
m, Ar─H), 7.39 (1H, d, J = 4.0 Hz, Ar─H), 7.45–7.50
(2H, m, Ar─H), 7.57 (1H, d, J = 8.0 Hz, Ar─H), 7.94–
7.97 (2H, m, Ar─H). ESI–MS m/z: 540 [M + Na]+.
Elemental Anal. Calcd (%) for C29H24FNO7: C, 67.31; H,
4.67; N, 2.71. Found: C, 67.08; H, 4.39; N, 2.55.
Ethyl
5-(3-(2,3-dioxoindolin-1-yl)propoxy)-2-(4-
methoxyphenyl)benzofuran-3-carboxylate (6f).
Yellow
1
solid, yield: 77%. H NMR (400 MHz, DMSO-d6) δ 1.33
(3H, t, J = 4.0 Hz, CO2CH2CH3), 2.13 (2H, t,
J = 4.0 Hz, ─CH2─), 3.86 (3H, s, OCH3), 3.88 (2H, t,
J = 4.0 Hz, ─CH2─), 4.12 (2H, t, J = 4.0 Hz, ─CH2─),
Ethyl
5-(3-(5-fluoro-2,3-dioxoindolin-1-yl)propoxy)-2-(4-
fluorophenyl)benzofuran-3-carboxylate (6b). Yellow solid,
Journal of Heterocyclic Chemistry
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Month 2019
Benzofuran–isatin Hybrids: Design, Synthesis, and In Vitro Anti-cancer Activities
4.34 (2H, q, J = 4.0 Hz, CO2CH2CH3), 6.96 (1H, dd,
J = 4.0, 8.0 Hz, Ar─H), 7.08–7.13 (3H, m, Ar─H), 7.24
(1H, d, J = 8.0 Hz, Ar─H), 7.40 (1H, d, J = 8.0 Hz,
Ar─H), 7.54–7.63 (3H, m, Ar─H), 7.96 (2H, d,
J = 8.0 Hz, Ar─H). ESI–MS m/z: 522 [M + Na]+.
Elemental Anal. Calcd (%) for C29H25NO7: C, 69.73; H,
5.04; N, 2.80. Found: C, 69.53; H, 4.87; N, 2.60.
Ar─H), 7.32–7.37 (2H, m, Ar─H), 7.58 (1H, d,
J = 8.0 Hz, Ar─H), 7.70 (1H, dd, J = 4.0, 8.0 Hz,
Ar─H), 7.95–7.97 (2H, m, Ar─H). ESI–MS m/z: 569
[M + Na]+. Elemental Anal. Calcd (%) for C30H27FN2O7:
C, 65.93; H, 4.98; N, 5.13. Found: C, 65.77; H, 4.72; N,
5.06.
Ethyl
5-(4-(5-fluoro-3-(ethoxyimino)-2-oxoindolin-1-yl)
propoxy)-2-(4-methoxyphenyl)benzofuran-3-carboxylate
Ethyl
5-(4-(5-methoxy-2,3-dioxoindolin-1-yl)butoxy)-2-(4-
1
(6k).
Yellow solid, yield: 49%. H NMR (400 MHz,
methoxyphenyl)benzofuran-3-carboxylate (6g).
Yellow
1
DMSO-d6) 1.29–1.39 (6H, m, NOCH2CH3 and
δ
solid, yield: 62%. H NMR (400 MHz, DMSO-d6) δ 1.32
(3H, t, J = 8.0 Hz, CO2CH2CH3), 1.80–1.84 (4H, m, 2×
─CH2─), 3.71–3.76 (5H, m, ─CH2─ and OCH3), 3.85
(3H, s, OCH3), 4.06 (2H, t, J = 8.0 Hz, ─CH2─), 4.33
(2H, q, J = 8.0 Hz, CO2CH2CH3), 6.96 (1H, dd, J = 4.0,
8.0 Hz, Ar─H), 7.08–7.16 (4H, m, Ar─H), 7.22–7.25
(1H, m, Ar─H), 7.42 (1H, d, J = 4.0 Hz, Ar─H), 7.55
(1H, d, J = 8.0 Hz, Ar─H), 7.94–7.97 (2H, m, Ar─H).
ESI–MS m/z: 566 [M + Na]+. Elemental Anal. Calcd (%)
for C31H29NO8: C, 68.50; H, 5.38; N, 2.58. Found: C,
68.27; H, 5.19; N, 2.33.
CO2CH2CH3), 2.10 (2H, t, J = 4.0 Hz, ─CH2─), 3.85
(3H, s, OCH3), 3.92 (2H, t, J = 4.0 Hz, ─CH2─), 4.08
(2H, t, J = 4.0 Hz, ─CH2─), 4.32 (2H, q, J = 8.0 Hz,
CO2CH2CH3), 4.48 (2H, q, J = 8.0 Hz, NOCH2CH3),
6.91 (1H, dd, J = 4.0, 8.0 Hz, Ar─H), 7.10 (2H, d,
J = 4.0 Hz, Ar─H), 7.20–7.23 (1H, m, Ar─H), 7.32–
7.37 (2H, m, Ar─H), 7.58 (1H, d, J = 8.0 Hz, Ar─H),
7.70 (1H, dd, J = 4.0, 8.0 Hz, Ar─H), 7.95–7.97 (2H, m,
Ar─H). ESI–MS m/z: 583 [M + Na]+. Elemental Anal.
Calcd (%) for C31H29FN2O7: C, 66.42; H, 5.21; N, 5.00.
Found: C, 66.19; H, 5.03; N, 4.87.
Ethyl
5-(4-(2,3-dioxoindolin-1-yl)butoxy)-2-(4-
methoxyphenyl)benzofuran-3-carboxylate (6h).
Yellow
Ethyl 5-(3-(5-methoxy-3-(methoxyimino)-2-oxoindolin-1-yl)
1
solid, yield: 68%. H NMR (400 MHz, CDCl3) δ 1.39
(3H, t, J = 8.0 Hz, CO2CH2CH3), 1.86–1.94 (4H, m, 2×
─CH2─), 3.78 (2H, t, J = 8.0 Hz, ─CH2─), 3.84 (3H, s,
OCH3), 4.04 (2H, t, J = 4.0 Hz, ─CH2─), 4.38 (2H, q,
J = 8.0 Hz, CO2CH2CH3), 6.85–6.91 (2H, m, Ar─H),
6.94–6.89 (2H, m, Ar─H), 7.06 (1H, t, J = 8.0 Hz,
Ar─H), 7.34 (1H, d, J = 12.0 Hz, Ar─H), 7.48 (1H, d,
J = 4.0 Hz, Ar─H), 7.50–7.53 (1H, m, Ar─H), 7.95–
7.99 (2H, m, Ar─H). ESI–MS m/z: 536 [M + Na]+.
Elemental Anal. Calcd (%) for C30H27NO7: C, 70.17; H,
5.30; N, 2.73. Found: C, 70.02; H, 5.11; N, 2.59.
propoxy)-2-phenylbenzofuran-3-carboxylate (6l).
Yellow
1
solid, yield: 83%. H NMR (400 MHz, DMSO-d6) δ 1.30
(3H, t, J = 8.0 Hz, CO2CH2CH3), 2.10 (2H, dd, J = 4.0,
8.0 Hz, ─CH2─), 3.74 (3H, s, OCH3), 3.90 (2H, t,
J = 8.0 Hz, ─CH2─), 4.08 (2H, t, J = 4.0 Hz, ─CH2─),
4.20 (3H, s, NOCH3), 4.34 (2H, q, J = 8.0 Hz,
CO2CH2CH3), 6.98 (1H, dd, J = 4.0, 8.0 Hz, Ar─H),
6.99–7.13 (2H, m, Ar─H), 7.39 (1H, d, J = 4.0 Hz,
Ar─H), 7.48 (1H, d, J = 4.0 Hz, Ar─H), 7.54–7.58 (3H,
m, Ar─H), 7.62 (1H, d, J = 8.0 Hz, Ar─H), 7.94–7.97
(2H, m, Ar─H). ESI–MS m/z: 551 [M + Na]+. Elemental
Anal. Calcd (%) for C30H28N2O7: C, 68.17; H, 5.34; N,
Ethyl
5-(4-(5-fluoro-3-(methoxyimino)-2-oxoindolin-1-yl)
propoxy)-2-phenylbenzofuran-3-carboxylate (6i).
Yellow
5.30. Found: C, 67.96; H, 5.09; N, 5.11.
1
solid, yield: 59%. H NMR (400 MHz, DMSO-d6) δ 1.32
(3H, t, J = 8.0 Hz, CO2CH2CH3), 2.10 (2H, t, J = 4.0 Hz,
─CH2─), 3.92 (2H, t, J = 4.0 Hz, ─CH2─), 4.08 (2H, t,
J = 4.0 Hz, ─CH2─), 4.21 (3H, s, NOCH3), 4.32 (2H, q,
J = 8.0 Hz, CO2CH2CH3), 6.94 (1H, dd, J = 4.0, 8.0 Hz,
Ar─H), 7.18–7.21 (1H, m, Ar─H), 7.30–7.32 (1H, m,
Ar─H), 7.38 (1H, d, J = 4.0 Hz, Ar─H), 7.53–7.61 (4H,
m, Ar─H), 7.68 (1H, d, J = 4.0 Hz, Ar─H), 7.93–7.96
(2H, m, Ar─H). ESI–MS m/z: 539 [M + Na]+. Elemental
Anal. Calcd (%) for C29H25FN2O6: C, 67.44; H, 4.88; N,
5.42. Found: C, 67.19; H, 4.67; N, 5.25.
Ethyl 5-(3-(5-methoxy-3-(methoxyimino)-2-oxoindolin-1-yl)
propoxy)-2-(4-methoxyphenyl)benzofuran-3-carboxylate
(6m). Yellow solid, yield: 59%. H NMR (400 MHz,
1
DMSO-d6) δ 1.32 (3H, t, J = 8.0 Hz, CO2CH2CH3), 2.09
(2H, dd, J = 4.0, 8.0 Hz, ─CH2─), 3.75 (3H, s, OCH3),
3.86–3.91 (5H, m, ─CH2─ and OCH3), 4.05–4.20 (5H,
m, ─CH2─ and NOCH3), 4.34 (2H, q, J = 8.0 Hz,
CO2CH2CH3), 6.94 (1H, dd, J = 4.0, 8.0 Hz, Ar─H),
7.01–7.11 (4H, m, Ar─H), 7.48 (1H, d, J = 4.0 Hz,
Ar─H), 7.56 (1H, d, J = 4.0 Hz, Ar─H), 7.62 (1H, d,
J = 8.0 Hz, Ar─H), 7.95–7.97 (2H, m, Ar─H). ESI–MS
m/z: 581 [M + Na]+. Elemental Anal. Calcd (%) for
C31H30N2O8: C, 66.66; H, 5.41; N, 5.02. Found: C,
66.51; H, 5.27; N, 4.86.
Ethyl
propoxy)-2-(4-methoxyphenyl)benzofuran-3-carboxylate
(6j).
5-(4-(5-fluoro-3-(methoxyimino)-2-oxoindolin-1-yl)
Yellow solid, yield: 79%. 1H NMR (400 MHz,
DMSO-d6) δ 1.32 (3H, t, J = 8.0 Hz, CO2CH2CH3), 2.10
(2H, t, J = 4.0 Hz, ─CH2─), 3.86 (3H, s, OCH3), 3.92
(2H, t, J = 4.0 Hz, ─CH2─), 4.08 (2H, t, J = 4.0 Hz,
─CH2─), 4.22 (3H, s, NOCH3), 4.34 (2H, q, J = 8.0 Hz,
CO2CH2CH3), 6.91 (1H, dd, J = 4.0, 8.0 Hz, Ar─H),
7.10 (2H, d, J = 4.0 Hz, Ar─H), 7.20–7.23 (1H, m,
Ethyl
5-(3-(5-methoxy-3-(ethoxyimino)-2-oxoindolin-1-yl)
propoxy)-2-(4-methoxyphenyl)benzofuran-3-carboxylate
(6n).
DMSO-d6) δ 1.30 (3H, J = 8.0 Hz, CO2CH2CH3), 2.11
(2H, t, J = 4.0 Hz, ─CH2─), 3.93 (2H, t, J = 4.0 Hz,
─CH2─), 4.03 (2H, t, J = 4.0 Hz, ─CH2─), 4.34 (2H, q,
1
Yellow solid, yield: 45%. H NMR (400 MHz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Q.-P. Diao, H. Guo, and G.-Q. Wang
Vol 000
J = 8.0 Hz, CO2CH2CH3), 4.45 (2H, q, J = 8.0 Hz,
NOCH2CH3), 6.90–7.09 (5H, m, Ar─H), 7.36–7.56 (3H,
m, Ar─H), 7.93–7.96 (2H, m, Ar─H). ESI–MS m/z: 595
[M + Na]+. Elemental Anal. Calcd (%) for C32H32N2O8:
C, 67.12; H, 5.63; N, 4.89. Found: C, 66.97; H, 5.52; N,
Ar─H), 7.16 (1H, d, J = 8.0 Hz, Ar─H), 7.37–7.42 (2H,
m, Ar─H), 7.52 (1H, d, J = 12.0 Hz, Ar─H), 7.86 (1H,
d, J = 8.0 Hz, Ar─H), 7.96 (2H, d, J = 8.0 Hz, Ar─H).
ESI–MS m/z: 565 [M + Na]+. Elemental Anal. Calcd (%)
for C31H30N2O7: C, 68.62; H, 5.57; N, 5.16. Found: C,
4.67.
68.43; H, 5.31; N, 5.02.
Ethyl 5-(3-(3-(methoxyimino)-2-oxoindolin-1-yl)propoxy)-2-
phenylbenzofuran-3-carboxylate (6o). Yellow solid, yield:
45%. H NMR (400 MHz, DMSO-d6) δ 1.29–1.38 (6H,
Ethyl 5-(4-(3-(ethoxyimino)-2-oxoindolin-1-yl)butoxy)-2-(4-
methoxyphenyl)benzofuran-3-carboxylate (6s).
Yellow
1
1
solid, yield: 53%. H NMR (400 MHz, CDCl3) δ 1.30–
1.39 (6H, m, NOCH2CH3 and CO2CH2CH3), 1.78–1.81
(4H, m, 2× ─CH2─), 3.79 (2H, t, J = 8.0 Hz, ─CH2─),
3.85 (3H, s, OCH3), 4.06 (2H, t, J = 4.0 Hz, ─CH2─),
4.33 (2H, q, J = 8.0 Hz, CO2CH2CH3), 4.46 (2H, q,
J = 8.0 Hz, NOCH2CH3), 6.95 (1H, dd, J = 4.0, 8.0 Hz,
Ar─H), 7.08–7.11 (3H, m, Ar─H), 7.18 (1H, d,
J = 8.0 Hz, Ar─H), 7.38–7.41 (2H, m, Ar─H), 7.56 (1H,
d, J = 8.0 Hz, Ar─H), 7.90 (1H, d, J = 8.0 Hz, Ar─H),
7.97 (2H, d, J = 8.0 Hz, Ar─H). ESI–MS m/z: 579
[M + Na]+. Elemental Anal. Calcd (%) for C32H32N2O7:
C, 69.05; H, 5.80; N, 5.03. Found: C, 68.77; H, 5.61; N,
4.96.
m, NOCH2CH3 and CO2CH2CH3), 2.08 (2H, dd, J = 4.0,
8.0 Hz, ─CH2─), 3.75 (3H, s, OCH3), 3.83–3.89 (5H, m,
─CH2─ and OCH3), 4.06 (2H, t, J = 4.0 Hz, ─CH2─),
4.20 (3H, s, NOCH3), 4.32 (2H, q, J = 8.0 Hz,
CO2CH2CH3), 4.45 (2H, q, J = 8.0 Hz, NOCH2CH3),
6.98–7.20 (3H, m, Ar─H), 7.40–7.62 (4H, m, Ar─H),
7.89–7.97 (3H, m, Ar─H). ESI–MS m/z: 521 [M + Na]+.
Elemental Anal. Calcd (%) for C29H26N2O6: C, 69.87; H,
5.26; N, 5.62. Found: C, 69.71; H, 5.06; N, 5.44.
Ethyl 5-(3-(3-(methoxyimino)-2-oxoindolin-1-yl)propoxy)-2-
(4-methoxyphenyl)benzofuran-3-carboxylate (6p).
Yellow
1
solid, yield: 68%. H NMR (400 MHz, CDCl3) δ 1.43
(3H, J = 8.0 Hz, CO2CH2CH3), 2.25 (2H, t, J = 4.0 Hz,
─CH2─), 3.90 (3H, s, OCH3), 4.02 (2H, t, J = 4.0 Hz,
─CH2─), 4.12 (2H, t, J = 4.0 Hz, ─CH2─), 4.31 (3H, s,
NOCH3), 4.43 (2H, q, J = 8.0 Hz, CO2CH2CH3), 6.92–
6.97 (2H, m, Ar─H), 7.01–7.07 (3H, m, Ar─H), 7.28–
7.33 (1H, m, Ar─H), 7.42 (1H, d, J = 8.0 Hz, Ar─H),
7.52 (1H, d, J = 4.0 Hz, Ar─H), 7.96 (1H, d, J = 8.0 Hz,
Ar─H), 8.02 (2H, d, J = 8.0 Hz, Ar─H). ESI–MS m/z:
551 [M + Na]+. Elemental Anal. Calcd (%) for
C30H28N2O7: C, 68.17; H, 5.34; N, 5.30. Found: C,
Anti-cancer activities. All the synthesized hybrids 6a–s
were investigated for their in vitro anti-cancer activity
against HepG2 (liver carcinoma), Hela (cervical cancer),
A549 (lung adenocarcinoma), DU145 (prostatic cancer),
SKOV3 (ovarian carcinoma), MCF-7 (breast cancer), and
drug-resistant
MCF-7/DOX
(doxorubicin-resistant
MCF-7) by SRB assay [20]. IC50 values were presented
as the concentration of drug inhibition 50% cell growth
and determined by at least three separate tests and reported.
67.95; H, 5.12; N, 5.09.
Ethyl 5-(3-(3-(ethoxyimino)-2-oxoindolin-1-yl)propoxy)-2-(4-
REFERENCES AND NOTES
methoxyphenyl)benzofuran-3-carboxylate (6q).
Yellow
1
solid, yield: 51%. H NMR (400 MHz, CDCl3) δ 1.31–
1.39 (6H, m, NOCH2CH3 and CO2CH2CH3), 2.11 (2H, t,
J = 8.0 Hz, ─CH2─), 3.86 (3H, s, OCH3), 3.93 (2H, t,
J = 8.0 Hz, ─CH2─), 4.08 (2H, t, J = 4.0 Hz, ─CH2─),
4.32 (2H, q, J = 8.0 Hz, CO2CH2CH3), 4.46 (2H, q,
J = 8.0 Hz, NOCH2CH3), 6.92 (1H, dd, J = 4.0, 8.0 Hz,
Ar─H), 7.07–7.11 (3H, m, Ar─H), 7.18 (1H, d,
J = 8.0 Hz, Ar─H), 7.38–7.43 (2H, m, Ar─H), 7.56 (1H,
d, J = 8.0 Hz, Ar─H), 7.92 (1H, d, J = 8.0 Hz, Ar─H),
7.97 (2H, d, J = 8.0 Hz, Ar─H). ESI–MS m/z: 565
[M + Na]+. Elemental Anal. Calcd (%) for C31H30N2O7:
C, 68.62; H, 5.57; N, 5.16. Found: C, 68.51; H, 5.39; N,
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1
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─CH2─), 3.78 (2H, t, J = 4.0 Hz, ─CH2─), 3.85 (3H, s,
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(1H, dd, J = 4.0, 8.0 Hz, Ar─H), 7.06–7.09 (3H, m,
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